1. Field of the Invention
The present invention relates to the use of S(+) ibuprofen to elicit an onset-hastened and enhanced anti-pyretic response in mammalian organisms in need of such treatment, and to certain pharmaceutical compositions comprising unit dosage effective amounts of S(+) ibuprofen.
2. Description of the Prior Art:
Ibuprofen, or (.+-.) 2-(p-isobutylphenyl)propionic acid, has the structural formula ##STR1##
The compound is well-known as a nonsteroidal anti-inflammatory drug having analgesic and antipyretic activity. Ibuprofen is currently marketed by prescription in the United States generically, as well as under tradenames such as Motrin.RTM., which is available in 400, 600 and 800 mg tablets for oral administration. Ibuprofen has recently also become available in this country in non-prescription strength (200 mg) under a variety of tradenames, including Advil.RTM. and Nuprin.RTM., as well as in generic form. For the treatment of mild to moderate pain, 400 mg every 4 to 6 hours, not to exceed 3200 mg daily, is generally recommended for Motrin.RTM.. The lower dose over-the-counter products are generally recommended for minor aches and pains, to be used orally at the 200 to 400 mg level, every 4 to 6 hours, not to exceed 1200 mg daily unless directed by a physician. See also Physician's Desk Reference, 40th edition, 1986, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, N.J. 07649, pp. 1854-1855 and 1897.
As is apparent from its chemical nomenclature, ibuprofen is a racemic mixture It is only the racemic mixture which has in fact ever been marketed There have, however, been some studies of the individual S(+) and R(-) isomers reported in the literature. These generally reflect that the R(-) isomer is rapidly converted to the S(+) enantiomer, which is the active form of ibuprofen.
Adams et al, Curr. Med. Res. Opin., 3, 552 (1975) and J. Pharm. Pharmaco., 28, 256-257 (1976), reported that in vivo anti-inflammatory and analgesic tests in guinea pigs, rats and mice comparing the dextro (+), levo (-) and racemic mixture forms of ibuprofen showed the three forms to be very similar in potency. (The in vivo tests were conducted in an acetylcholine-induced writhing test in the mouse, in a pain threshold technique test using the yeast-inflamed paw of the rat and using ultraviolet erythema in the guinea pig.) In vitro, however, it was found that nearly all of the activity resided in the dextrorotatory form. The authors concluded that the in vitro results suggested that the dextro (+) form was the active one, but that in vivo the levo form was converted to the dextro form so that there was little difference in pharmacological activity. This was also seen to be an explanation for earlier observations [Adams et al, J. Pharm. Sci., 56, 1686 (1967) and Mills et al, Xenobiotica, 3, 589-598 (1973)] that ibuprofen's urinary metabolites in man were found to be dextrorotatory. Thus, it has been recognized for over a decade that the S(+) isomer is the active form.
Wechter et al, Biochem. Biophys. Res. Commun., 61, 833-837 (1974) reported the results of tests in healthy human subjects designed to determine the stereochemistry involved in ibuprofen's metabolism and the relative stereochemical relationships between ibuprofen's optical isomers and its metabolic products. They found there was a facile epimerization of ibuprofen's R(-) isomer to the S(+) isomer and concluded that this accounted for the essential bioequivalence of the R(-) and S(+) isomers.
Related observations were reported by Vangiessen et al, J. Pharm. Sci., Vol 64, No. 5, 798-801 (May 1975), Who found that after oral administration of the racemic mixture to human volunteers, the predominant enantiomer in the peripheral circulation and excreted in the urine was of the d-configuration. Vangiessen et al estimated that the plasma drug disappearance half-lives for the d- and l-isomer were 3.34 and 2.01 hours, respectively The concentration ratio of d to l increased progressively with time from 1.17 at one hour to 2.65 at eight hours; however, these estimates are compromised by the small sample size (n=3), the fact that normal subjects were used, and the extremely large standard deviations from the mean at the earliest (one-hour) post-dosing time point. Interpretation of the results of this study is further compromised because S(+) was not administered alone so that no comparisons with the racemate are possible.
Subsequently, Kaiser et al., J. Pharm. Sci., Vol. 65 No. 2, 269-273 (February 1976) reported on characterization of enantiomeric compositions of ibuprofen's major urinary metabolites after oral administration of the racemic mixture and the individual S(+) and R(-) isomers to healthy human subjects. It was found that only the R(-) enantiomer of the intact drug was inverted to its optical antipode, S(+).
Hutt et al, J. Pharm. Pharmacol., 35, 693-704 (1983), reviewed the earlier work on the metabolic chiral inversion of 2-arylpropionic acids, including ibuprofen, which they indicate was the first substituted 2-arylpropionic acid conclusively shown to undergo the inversion as well as the most studied member of the group. The authors again noted that Adams et al (1976) found no significant difference in in vivo activity among the R(-) and S(+) isomers and the racemic mixture in three different animal models, but very large differences in vitro between the R(-) and S(+) isomers, ascribing this discrepancy to the virtually quantitative conversion of the R(-) to the active S(+) isomer in vivo. Hutt et al indicated similar properties for fenoprofen. The enantiomers of fenoprofen were reported to be of equal potency in animal test systems.
In the same paper, Hutt et al reported that, in contrast, for several other 2-arylpropionic acids, the inactive R(-) isomer was not converted in vivo to the active S(+) isomer as readily as ibuprofen and fenoprofen, although the conversion seemed to occur to some extent over time. Naproxen, they noted, has been the only compound marketed as the S(+) enantiomer to date. And in the case of indoprofen, the R(-) enantiomer was found to be about 20 times less pharmacologically active in rats and mice in vivo than the S(+) isomer. Hutt et al concluded:
It is likely that benefits will be obtained from the use of the S(+)-enantiomer of 2-arylpropionates as drugs as opposed to the racemates. This is only found at present in the case of naproxen In cases of rapid inversion, the inactive R(-) isomer serves merely as a prodrug for the active S(+)-antipode. Where inversion is slow, the R(-) enantiomer is an unnecessary impurity in the active S(+) form. Use of the S(+)-enantiomer would permit reduction of the dose given, remove variability in rate and extent of inversion as a source of variability in therapeutic response and would reduce any toxicity arising from non-stereospecific mechanisms.
Thus, in cases of rapid inversion, such as ibuprofen and fenoprofen, where substantially equivalent in vivo responses have been reported for the individual enantiomers and the racemic drug, Hutt et al suggested that no benefits would be obtained from the use of the S(+) isomer because the inactive R(-) isomer merely acts as a prodrug for the active S(+) form. Contrariwise, in cases where chiral inversion is slow, e.g. naproxen and indoprofen, the use of the S(+) enantiomer is desirable for several reasons enumerated by Hutt et al. Indeed, naproxen has been reported to be marketed as the d-isomer for one of the reasons given by Hutt et al, i.e. to reduce side effects (Allison et al "Naproxen," Chapter 9 in Anti-inflammatory and Anti-Rheumatic Drugs, eds. Rainsford and Path, CRC Press Inc., Boca Raton, Fla., 1985, p 172).
Another general report on earlier work has been provided by Hutt et al in Clinical Pharmacokinetics, 9, 371-373 (1984). In this article on the importance of stereochemical considerations in the clinical pharmacokinetics of 2-arylpropionic acids, the authors tabulated relative potencies of the enantiomers of a number of 2-arylpropionic acids in vivo and in vitro. The in vitro results showed the S or (+) isomer in each case to be the active species. In vivo however, the results were not consistent across the entire class. Thus, the results for naproxen and indoprofen demonstrate the S or (+) isomer to be much more active in vivo indicating a relatively slow inversion of the inactive R or (-) isomer to the active S or (+) isomer; the results for fenoprofen and ibuprofen, on the other hand, demonstrate the inactive R or (-) and the active S or (+) isomers to be approximately equally effective in vivo, indicating a rapid inversion of R or (-) isomer to S or (+) isomer.
The medicinal chemistry of 2-arylpropionic acids and other NSAIDs (non-steroidal anti-inflammatory drugs) has been reviewed by Shen in Angewandte Chemie International Edition, Vol. 11, No. 6, 460-472 (1972) and in "Nonsteroidal Anti-Inflammatory Agents," Chapter 62 in Burger's Medicinal Chemistry, 4th edition, part III, Wiley Interscience, New York (1981), pp. 1205-1271. In the latter publication, Shen notes that ibuprofen is used as a racemic mixture because the two optical isomers are equally potent in the UV erythema assay, a commonly used anti-inflammatory model.
Lee et al, Br. J. Clin. Pharmac. 19, 669-674 (1985), administered racemic ibuprofen and each of the enantiomers separately to four healthy human males, then studied stereo-selective disposition. They estimated that about 63% of the dose of R(-) was inverted to the S(+) enantiomer over a 14 hour period. Lee et al noted that the kinetics of the S(+) and R(-) enantiomers were changed when the respective optical antipode was concurrently administered. The authors speculated that this alteration reflected an interaction between the R(-) and S(+) forms at the binding sites for plasma protein. An ibuprofen plasma level time profile for a single subject is shown graphically in the paper and might suggest that there was minimal conversion in the early hours of the study, but the authors did not appear to attach any significance to this. Lee et al indicated that the half-life of S(+) after administering the racemate was 2.5 hours, whereas the half-life of S(+) after administering S(+) was 1.7 hours. The authors recognized the limitations of their work, for reasons including the small number of subjects studied, and an assumption that the clearance of S(+) is unchanged between administrations of R(-) and S(+). They also cautioned that it is quite likely that the fraction of R(-) that is inverted to S(+) varies from individual to individual.
Cox et al, J. Pharmacol. Exp. Ther., Vol. 232, No. 3, 636-643 (1985), carried out liver perfusion experiments to study the role of the liver in the clearance of the stereoisomers of ibuprofen in normal and disease states. Experiments were conducted with normal and fatty rat liver. Results showed that when liver is fatty, clearance of the R(-) isomer is affected and preferential S(+) hepatic distribution is eliminated. However, the effects were predicted to have only minimal impact on total ibuprofen plasma levels following racemic ibuprofen dosing.
Cox et al, abstract in Amer. Soc. Clin. Pharmacol. Ther., February 1987, 200 (abstract PIIL-7) described a three way crossover study in which single doses of ibuprofen solution were given orally to twelve healthy human males. The doses given were 800 mg of racemic ibuprofen, 400 mg of R(-) ibuprofen and 400 mg of S(+) ibuprofen. Based on area-under-the-curve measures, significant chiral inversion was observed for R(-) but not for S(+). Elimination of S(+) was inhibited as plasma concentration of R:S increased. The extent of R(-) inversion, based on urinary data, was the same for the racemate and the R(-) isomer, with a mean of 0.66. Again, the authors gave no information as to what occurred in the first two hours. The statement on reduced clearance of S(+) in the racemate is consistent with the finding of increased length of S(+) half-life after administering the racemate found by Lee et al.
Laska et al, Clin. Pharmacol. Ther., Vol. 40, No. 1, 1-7 (July 1986), reported that administration of racemic ibuprofen to patients with moderate to severe pain subsequent to third molar extraction gave correlations between pain intensity ratings and serum levels of ibuprofen. Correlations were found between contemporaneous serum levels and measures of pain intensity improvement, supporting the proposition that increased ibuprofen serum levels lead to increased analgesia, particularly in the first few hours after dosing. However, the authors did not correlate analgesia with either isomer of ibuprofen; the possibility of critical differences between free and bound ibuprofen and between the S(+) and R(-) isomers was not addressed.
In summary, the current state of the art recognizes that, in mammals, the S(+) form is the active enantiomer of ibuprofen. The art further recognizes that there is a significant, relatively rapid conversion in vivo of R(-) to S(+), with little if any conversion of S(+) to R(-) Furthermore, in the only animal experiments on efficacy reported in the literature, it was noted that there were no significant differences in potency between the racemate and the enantiomers. This is attributed to the rapidity of the chiral inversion. This would suggest there would be no benefit to be derived from the use of S(+) ibuprofen for analgesia or reducing elevated body temperature. Indeed, use of S(+) alone would appear to reduce the half-life of the active drug. The prior art, moreover, is conspicuously silent in respect to any onset-hastened/enhanced alleviation of mammalian fever utilizing whatever form of the ibuprofen drug species.